Focal hole versus screw stimulation to prevent false negative results in detecting pedicle breaches during spinal instrumentation

ObjectiveWe describe a stimulus-evoked EMG approach to minimize false negative results in detecting pedicle breaches during lumbosacral spinal instrumentation.MethodsIn 36 patients receiving 176 lumbosacral pedicle screws, EMG threshold to nerve root activation was determined using a focal probe inserted into the pilot hole at a depth, customized to the individual patients, suitable to position the stimulating tip at the point closest to the tested nerve root. Threshold to screw stimulation was also determined.ResultsMean EMG thresholds in 161 correctly fashioned pedicle instrumentations were 7.5 mA ± 2.46 after focal hole stimulation and 21.8 mA ± 6.8 after screw stimulation. Direct comparison between both thresholds in individual pedicles showed that screw stimulation was always biased by an unpredictable leakage of the stimulating current ranging from 10 to 90%. False negative results were never observed with hole stimulation but this was not true with screw stimulation.ConclusionsFocal hole stimulation, unlike screw stimulation, approaches absolute EMG threshold as shown by the lower normal limit (2.6 mA; p < 0.05) that borders the upper limit of threshold to direct activation of the exposed root.SignificanceThe technique provides an early warning of a possible pedicle breakthrough before insertion of the more harmful, larger and threaded screw.     

Safety profile of the adjuvanted recombinant zoster vaccine: Pooled analysis of two large randomised phase 3 trials

Background

The ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229) phase 3 clinical trials showed that the adjuvanted recombinant zoster vaccine (RZV) was ≥90% efficacious in preventing herpes zoster in adults. Here we present a comprehensive overview of the safety data from these studies.

Modification of the vaccine manufacturing process improves the pyrogenicity profile of inactivated influenza vaccines in young children

Background

There were increased reports of fevers and febrile reactions in young children (particularly children aged <5?years) receiving the Seqirus/CSL Southern Hemisphere 2010 trivalent inactivated influenza vaccine (IIV3). Modifying the vaccine manufacturing process by increasing the minimum concentration of splitting agent (sodium taurodeoxycholate [TDOC]) from 0.5% w/v to 1.5% w/v for all strains resolved this issue. The current analysis compared fever rates in three pediatric studies of Seqirus IIV3 (S-IIV3) or quadrivalent inactivated influenza vaccine (S-IIV4), prepared using the modified manufacturing process, with fever rates in three pediatric studies of historical (pre-2010) IIV3 formulations. The historical IIV3 formulations, S-IIV3, and S-IIV4 had 0/3, 2/3, and 4/4 vaccine strains split at 1.5% TDOC, respectively.

Nephrotic syndrome following four-component meningococcal B vaccination: Epidemiologic investigation of a surveillance signal

BackgroundIn May 2014, a mass vaccination campaign with four-component meningococcal serogroup B (4CMenB) vaccine was launched in a localized region of Quebec, Canada experiencing high invasive meningococcal B disease endemicity. Active post-marketing surveillance identified several cases of nephrotic syndrome (NS) among ∼49,000 vaccinated individuals aged 2 months to 20 years. We report the epidemiologic investigation of this potential vaccine safety signal.MethodsActive vaccine safety surveillance was conducted electronically, with participants completing an online questionnaire prompted at 7 days after each dose and 6 months following the last dose. Additional NS cases were sought from provincial hospitalization and emergency room databases.ResultsIn the year following the first dose of 4CMenB vaccination, four confirmed NS cases (three hospitalized) were identified among vaccinated children 2–5-years-old with onset several months post-vaccination. None had renal biopsy but given their age, and positive response to steroids, idiopathic NS was presumptively diagnosed. Among vaccinated children 1–9-years-old, the NS incidence in the year post-vaccination was 17.7 per 100,000 (1 per 5650 vaccinees) with an NS hospitalization rate (i.e. excluding the outpatient case) that was 3.6-fold higher (95%CI = 0.7–11.8; p = 0.12) than the rest of the province for the same period, and 8.3-fold greater (95%CI = 1.1–62.0; p = 0.039) than during the eight years preceding the immunization campaign in the affected region.ConclusionActive safety surveillance identified an unexpected increase in NS incidence following 4CMenB vaccination. Further epidemiological investigation identified four vaccinated cases in total over a 12 month period of follow up. The greater risk in vaccinees had wide confidence intervals with he lower limit including or just above the nul value, an observation with no or marginal statistical significance. The temporal association with vaccination may be explained by other causes and/or chance clustering of a rare event unrelated to vaccination. To confirm or refute a potential link to vaccination, surveillance in other jurisdictions administering 4CMenB to children 1–9-years-old is needed.     

Stabilization and formulation of a recombinant Human Cytomegalovirus vector for use as a candidate HIV-1 vaccine

Live attenuated viral vaccine/vector candidates are inherently unstable and infectivity titer losses can readily occur without defining appropriate formulations, storage conditions and clinical handling practices. During initial process development of a candidate vaccine against HIV-1 using a recombinant Human Cytomegalovirus vector (rHCMV-1), large vector titer losses were observed after storage at 4 °C and after undergoing freeze-thaw. Thus, the goal of this work was to develop candidate frozen liquid formulations of rHCMV-1 with improved freeze-thaw and short-term liquid stability for potential use in early clinical trials. To this end, a virus stability screening protocol was developed including use of a rapid, in vitro cell-based immunofluorescence focus assay to quantitate viral titers. A library of ∼50 pharmaceutical excipients (from various known classes of additives) were evaluated for their effect on vector stability after freeze-thaw cycling or incubation at 4 °C for several days. Certain additives including sugars and polymers (e.g., trehalose, sucrose, sorbitol, hydrolyzed gelatin, dextran 40) as well as removal of NaCl (lower ionic strength) protected rHCMV-1 against freeze-thaw mediated losses in viral titers. Optimized solution conditions (e.g., solution pH, buffers and sugar type) slowed the rate of rHCMV-1 titer losses in the liquid state at 4 °C. After evaluating various excipient combinations, three new candidate formulations were designed and rHCMV-1 stability was benchmarked against both the currently-used and a previously reported formulation. The new candidate formulations were significantly more stable in terms of reducing rHCMV-1 titer losses after 5 freeze-thaw cycles or incubation at 4 °C for 30 days. This case study highlights the utility of semi-empirical design of frozen liquid formulations of a live viral vaccine candidate, where protection against infectivity titer losses due to freeze-thaw and short-term liquid storage are sufficient to enable more rapid initiation of early clinical trials.     

Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences

Estradiol, either from peripheral or central origin, activates multiple molecular neuroprotective and neuroreparative responses that, being mediated by estrogen receptors or by estrogen receptor independent mechanisms, are initiated at the membrane, the cytoplasm or the cell nucleus of neural cells. Estrogen-dependent signaling regulates a variety of cellular events, such as intracellular Ca²⁺ levels, mitochondrial respiratory capacity, ATP production, mitochondrial membrane potential, autophagy and apoptosis. In turn, these molecular and cellular actions of estradiol are integrated by neurons and non-neuronal cells to generate different tissue protective responses, decreasing blood-brain barrier permeability, oxidative stress, neuroinflammation and excitotoxicity and promoting synaptic plasticity, axonal growth, neurogenesis, remyelination and neuroregeneration. Recent findings indicate that the neuroprotective and neuroreparative actions of estradiol are different in males and females and further research is necessary to fully elucidate the causes for this sex difference.     

Effects of newly introduced antidiabetic drugs on autophagy

Diabetes mellitus is a chronic metabolic disorder that has a complex molecular and cellular pathophysiology, resulting in its dynamic progression and that may show differing responses to therapy. The incidence of diabetes mellitus increases with age and requires additive therapeutic agents for its management. SGLT2i and DPP-4 inhibitors and GLP-1 receptor agonists (GLP-1RA) are newly introduced antidiabetic drugs that work through differing mechanisms; DPP-4 inhibitors maintain the endogenous level of GLP1; GLP-1RA result in pharmacological levels of GLP1, whilst SGLT2i act on the proximal tubules of the kidney. They have shown efficacy in the management of diabetes and in contrast to other antidiabetic drugs, do not inherently cause hypoglycemia in therapeutic doses. Autophagy as a highly conserved mechanism to maintain cell survival and homeostasis by degradation of damaged or aged organelles and components, and recognised to be increasingly important in diabetes. In the present review, we discuss the modulatory effects of these newly introduced antidiabetic drugs on the autophagy process.     

基于“气道神经源性炎症-TRP通路”探讨慢性咳嗽发病机制及中医治疗

咳嗽临床常见，尤其是胸部影像学无明显异常的慢性咳嗽，病因复杂、易误诊误治，逐渐受到重视，国内外相继颁发相关指南，目前认为咳嗽高敏感性是其重要的病理生理机制。中医将慢性咳嗽归于"久咳""久嗽"范畴，在病因病机、治法方药上积累了丰富的临床经验，史利卿教授团队针对该病开展了专项临床及基础研究15年，根据传统中医理论及其突出临床症状提出"风邪伏肺"病机，应用祛风宣肺法治疗效果显著。文章结合西医学相关咳嗽机制研究进展及既往研究结果，初步探讨祛风宣肺法治疗该病的疗效机制，丰富慢性咳嗽风邪伏肺致咳相关学术理论的科学内涵，有利于提高中医药防治慢性咳嗽学术水平。     

针灸联合西药对中重度间歇性过敏性鼻炎患者T淋巴细胞亚群、IL-4、IL-10、VACM-1水平的影响

目的观察针灸联合西药对中重度间歇性过敏性鼻炎患者血清T淋巴细胞亚群、炎性因子及血管细胞黏附分子-1(VACM-1)的影响。方法将120例中重度间歇性过敏性鼻炎患者随机分为对照组和治疗组,每组60例。对照组予丙酸氟替卡松鼻喷雾剂、盐酸氮卓斯汀片治疗,治疗组在对照组治疗措施的基础上加用针灸疗法。两组疗程均为28天,观察临床疗效,比较中医证候积分、血清T淋巴细胞亚群、炎性因子[白介素-4(IL-4)、白介素-10(IL-10)]及VACM-1水平的变化情况。结果①治疗组、对照组总有效率分别为95.0%、81.7%,治疗组临床疗效优于对照组(P0.05)。②治疗前与疗程结束后7天组内比较,两组中医证候(鼻塞不通、鼻痒难耐、鼻流清涕、喷嚏频作)较治疗前改善(P0.05);组间疗程结束后7天比较,治疗组中医证候改善情况优于对照组(P0.05)。③治疗前与疗程结束后7天组内比较,两组血清CD3~+、CD4~+水平和CD4~+/CD8~+较治疗前升高(P0.05),血清CD8~+、IL-4、IL-10、VCAM-1水平较治疗前降低(P0.05);组间疗程结束后7天比较,上述指标差异有统计学意义(P0.05)。结论针灸联合西医治疗中重度间歇性过敏性鼻炎疗效满意,可有效缓解患者的临床症状,改善机体免疫状态,减轻炎症反应。